Parkinson's disease (PD) is a chronic and progressive neurodegenerative disorder with symptoms such as resting tremor, rigidity, bradykinesia and postural instability. These symptoms are largely caused by progressive loss of dopaminergic neurons in the substantia nigra compacta, which ultimately reduces dopaminergic input to the striatum and other brain regions.1 Medications for treating PD symptoms are typically orally administered in the form of tablets or capsules containing active pharmaceutical ingredient levodopa or pramipexole amongst others such as ropinirole, amantadine, catechol-omethyl transferase (COMT) inhibitors, rasagiline, rotigotine and biperidine. 1 Ferrer I, Martinez A, Blanco R, Dalfo'E, Carmona M (2011) Neuropathology of sporadic Parkinson disease before the appearance of parkinsonism: preclinical Parkinson disease. J Neural Transm 118: 821-839
Levodopa (L-dihydroxyphenylalanine or L-dopa) is a dopamine precursor which is administered with carbidopa, a dopa-decarboxylase (DDC) inhibitor, so that the levodopa is decarboxylated substantially within the central nervous system. However, with extended use of levodopa, fluctuations in motor control can occur with increasing frequency and severity, eventually disabling the patient.
Pramipexole is a member of the class of drugs known as dopamine agonists that may be administered concurrently with levodopa to help alleviate the fluctuations in motor control. Dopamine agonists (DAs) are synthetic agents which directly stimulate dopamine receptors and are used either in monotherapy for the treatment of the motor symptoms of PD in the early stage of the disease or in the later phase of the disease to lessen motor complications associated with levodopa therapy.
Although PD medications are typically in the form of tablets and capsules, transdermal patches offer an alternative form of administration. Specifically, compared to tablets and capsules, transdermal patches provide reduced dosing frequency, prolonged therapeutic duration, avoidance of gastrointestinal absorption as well as hepatic first-pass metabolism, minimized fluctuation in plasma drug concentrations, noninvasive administration with advantages over the oral route of administration, easy termination of drug administration by simply removing the patch from the skin and improved patient compliance.2, 3 2 Prausnitz M, Langer R., Transdermal drug delivery, Nat Biotechnology. 2008 November; 26(11): 1261-12683 Gaikwad A., Transdermal drug delivery system: Formulation aspects and evaluation, Comprehensive Journal of Pharmaceutical Sciences. February 2013, Vol. 1(1), pp. 1-10
With respect to improved patient compliance, the transdermal patch is particularly beneficial to PD patients in comparison to tablets or capsules. The reason is that PD tablets and capsules require multiple daily doses in contrast with the transdermal patch which is capable of providing prolonged therapeutic duration with just one single application, simplifying dosing regimen and, thereby, facilitating patient compliance. In addition, a patient can easily forget whether he or she has already taken a capsule or tablet whereas, in contrast, a patient can easily tell whether a new transdermal patch has been applied, making it easier for a patient to follow required dosing regimen. Dosing regimen compliance in the patients with PD is particularly important since PD is a progressive, neurological disease that requires lifelong treatment. The simplified drug regimen would substantially improve the quality of life of the PD patients as well as their caregivers.
Published patent applications CN 103432104, Tingting Pu et al. AAPS Pharma Sci Tech 2016 published online May 31, 2016 and US 2016/0113908, the disclosures of which are incorporated herein by reference, each disclose pramipexole transdermal patches applied for therapeutic duration over multiple days use, the former two references describing use over a five to seven day period per patch application while the latter US publication describes a therapeutic use ranging from at least two days through one hundred sixty eight hours (seven days) per patch. This publication also references in paragraph 0073 that the acrylic base adhesive is preferably based on acrylates lacking a carboxylic acid functional group.
Although week-long pramipexole transdermal patches provide substantially simpler dosaging regimen in comparison to tablets and capsules, the prolonged therapeutic duration can itself create challenges. For example, a week-long pramipexole transdermal patch requires high drug loading that increases potential risks with respect to toxicity and dose dumping. In addition, by design, the high drug loading and prolonged therapeutic duration dictate that the patches do not allow moisture to pass through since moisture enhances the likelihood of pramipexole crystallization. A transdermal patch on a patient's skin that does not permit for moisture pass through for a days at a time may cause skin irritation that may become severe.4 Moreover, from a practical point of view, requiring a transdermal patch to be applied to the skin for days at a time may also be an obstacle in the way of a patient's other daily needs such as showers or baths. Therefore, a pramipexole transdermal patch with therapeutic duration of about 24 hours, or a daily pramipexole transdermal patch, may provide advantages for administering pramipexole not only as compared to tablets and capsules but also compared to transdermal patches of week-long duration. 4 Paude K., Milewski M., Swadley C., Brogden N., Ghosh P. and Stinchcomb A., Challenges and opportunities in dermal/transdermal delivery, NIH Public Access; 2010 Jul. 1{grave over ( )} (1): 109-131
There exists a commercially available transdermal patch for daily administration that provides a dopamine agonist for treating PD called Neupro® transdermal patch that contains rotigotine as the active pharmaceutical ingredient. However, it has been reported that rotigontine presents a higher risk of hypotension and somnolence in comparison with pramipexole.5 In addition, U.S. Pat. No. 7,344,733 refers to transdermal pramipexole and ropintrole patches and references product deficiencies of a pramipexole patch described in EP-B1-0 428 038 in terms of very rapid decomposition of the active ingredient accompanied by discoloration and the pramipexole crystallization. The '733 patent describes the use of acrylate monomer adhesives alone or polymerized with functional monomers. However, none of the listed acrylates use adhesive admixtures contain both a functional hydroxyl and carboxylic acid group. 5 Etminan M, Gill S and Samil A., Comparison of the risk of adverse events with pramipexole and ropinirole in patients with Parkinson's disease: a meta-analysis, Drug Saf, 2003; 26(6):439-44
Therefore, it is an object of the invention to provide a pramipexole transdermal patch for daily administration with minimal pramipexole blood concentration fluctuations. It is another object of the invention to provide a pramipexole transdermal patch with high flux and low pramipexole crystallization.